| Indications and Usage, Treatment of Mildly to Moderately Active Ulcerative Colitis (1.1) || 04/2014 |
| Dosage and Administration, Dosage for Treatment of Mildly to Moderately Active Ulcerative Colitis (2.1) || 04/2014 |
| Dosage and Administration, Dosage for Treatment of Mildly to Moderately Active Ulcerative Colitis (2.1) || 10/2014 |
| Dosage and Administration, Dosage for Maintenance of Remission of Ulcerative Colitis (2.2) || 10/2014 |
| Dosage and Administration, Important Administration Instructions (2.3) || 04/2014 |
| Dosage and Administration, Testing Prior to DELZICOL Administration (2.4) || 04/2014 |
1 INDICATIONS AND USAGE DELZICOL is an aminosalicylate indicated for: Treatment of mildly to moderately active ulcerative colitis in patients 12 years of age and older (1.1) Maintenance of remission of ulcerative colitis in adults (1.2) 1.1 Treatment of Mildly to Moderately Active Ulcerative Colitis DELZICOL® (mesalamine) delayed-release capsules are indicated for the treatment of mildly to moderately active ulcerative colitis in patients 12 years of age and older. 1.2 Maintenance of Remission of Ulcerative Colitis in Adults DELZICOL® (mesalamine) delayed-release tablets are indicated for the maintenance of remission of ulcerative colitis in adults. The safety and effectiveness of DELZICOL for the maintenance of remission of ulcerative colitis in pediatric patients have not been established.
| Weight Group (kg) || Daily Dose (mg/kg/day) || Maximum Daily Dose (grams/day) |
| 17 to < 33 || 36 to 71 || 1.2 |
| 33 to < 54 || 37 to 61 || 2.0 |
| 54 to 90 || 27 to 44 || 2.4 |
3 DOSAGE FORMS AND STRENGTHS DELZICOL (mesalamine) delayed-release capsules are red capsules containing 400 mg mesalamine and imprinted with “WC 400mg” in white. Delayed-release capsules: 400 mg (3)
4 CONTRAINDICATIONS DELZICOL is contraindicated in patients with known hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of DELZICOL [see Warnings and Precautions (5.3), Adverse Reactions (6.2), and Description (11)]. Patients with known hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of DELZICOL capsules (4, 5.3)
5 WARNINGS AND PRECAUTIONS Renal Impairment (for example, minimal change nephropathy, acute and chronic interstitial nephritis, renal failure): Assess renal function at beginning of treatment and periodically during treatment (5.1) Mesalamine-induced Acute Intolerance Syndrome: Has been reported. Observe patients closely for worsening of these symptoms while on treatment (5.2) Hypersensitivity Reactions: Use caution when treating patients who are hypersensitive to sulfasalazine. Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported (5.3) Hepatic Failure: Has been reported in patients with pre-existing liver disease. Use caution when treating patients with liver disease (5.4) Prolonged Gastric Retention in Patients with Upper Gastrointestinal Obstruction: May lead to a delay in onset of action (5.5) 5.1 Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and renal failure, has been reported in patients taking products such as DELZICOL that contain mesalamine or are converted to mesalamine. It is recommended that patients have an evaluation of renal function prior to initiation of DELZICOL and periodically while on therapy. Prescribers should carefully evaluate the risks and benefits when using DELZICOL in patients with known renal impairment or history of renal disease [see Drug Interactions (7.1) and Nonclinical Toxicology (13.2)]. 5.2 Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, abdominal pain, bloody diarrhea, and sometimes fever, headache, and rash. Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with DELZICOL. 5.3 Hypersensitivity Reactions Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to DELZICOL or to other compounds that contain or are converted to mesalamine. Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with DELZICOL and other mesalamine medications. Caution should be taken in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis. 5.4 Hepatic Failure There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering DELZICOL to patients with liver disease. 5.5 Prolonged Gastric Retention in Patients with Upper Gastrointestinal Obstruction Organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of DELZICOL which would delay release of mesalamine in the colon.
6 ADVERSE REACTIONS The most serious adverse reactions seen in DELZICOL clinical trials or with other products that contain or are metabolized to mesalamine are: Renal impairment, including renal failure [see Warnings and Precautions (5.1)] Acute intolerance syndrome [see Warnings and Precautions (5.2)] Hypersensitivity reactions [see Warnings and Precautions (5.3)] Hepatic failure [see Warnings and Precautions (5.4)] The data presented in Section 6.1 are from clinical trials conducted with mesalamine delayed-release tablets. DELZICOL is bioequivalent to these mesalamine delayed-release tablets. The most common adverse reactions (observed in greater than or equal to 5% of adults in clinical trials) were abdominal pain, eructation, pain, back pain, rash, dyspepsia, rhinitis, flu syndrome, asthenia, flatulence, vomiting, fever, arthralgia, constipation, and gastrointestinal bleeding (6.1) Adverse reactions in children were similar (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Warner Chilcott at 1-800-521-8813 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In total, mesalamine delayed-release 400 mg tablets have been evaluated in 2690 patients with ulcerative colitis in controlled and open-label trials. Adverse events presented in the following sections may occur regardless of length of therapy and similar events have been reported in short- and long-term studies and in the postmarketing setting. Clinical studies supporting mesalamine delayed-release tablets use for the treatment of mildly to moderately active ulcerative colitis included two 6-week, placebo-controlled, randomized, double-blind studies in adults with mildly to moderately active ulcerative colitis (Studies 1 and 2), and one 6-week, randomized, double-blind, study of 2 dose levels in children with mildly to moderately active ulcerative colitis. Clinical studies supporting the use of mesalamine delayed-release tablets in the maintenance of remission of ulcerative colitis included a 6-month, randomized, double-blind, placebo-controlled, multi-center study and four active-controlled maintenance trials comparing mesalamine delayed-release with sulfasalazine. Mesalamine delayed-release tablets have been evaluated in 427 adults and 82 children with ulcerative colitis in these controlled studies. Treatment of Mildly to Moderately Active Ulcerative Colitis in Adults In two 6-week placebo-controlled clinical studies (Studies 1 and 2) involving 245 patients, 155 of whom were randomized to mesalamine delayed-release tablets [see Clinical Studies (14.1)], 3.2% of the mesalamine delayed-release tablets-treated patients discontinued therapy because of adverse reactions as compared to 2.2% of the placebo-treated patients. The average age of patients in Study 1 was 42 years and 48% of patients were male. The average age of patients in Study 2 was 42 years and 59% of patients were male. Adverse reactions leading to withdrawal from mesalamine delayed-release tablets included (each in one patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache; rash, lethargy and constipation; dry mouth, malaise, lower back discomfort, mild disorientation, mild indigestion and cramping; headache, nausea, aching, vomiting, muscle cramps, a stuffy head, plugged ears, and fever. Adverse reactions in patients treated with mesalamine delayed-release tablets occurring at a frequency of at least 2% and at a rate greater than placebo in 6-week, double-blind, placebo-controlled trials (Studies 1 and 2) are listed in Table 1 below. Table 1: Adverse Reactions Reported in Two Six-Week Placebo-Controlled Trials (Studies 1 and 2) Experienced by at Least 2% of patients in the mesalamine delayed-release tablets Group and at a Rate Greater than Placebo % of Patients with Adverse Reactions Adverse Reaction mesalamine delayed-release tablets Placebo (n = 152) (n = 87) Abdominal pain 18 14 Eructation 16 15 Pain 14 8 Back pain 7 5 Rash 6 3 Dyspepsia 6 1 Arthralgia 5 3 Vomiting 5 2 Constipation 5 1 Chest pain 3 2 Chills 3 2 Peripheral edema 3 2 Myalgia 3 1 Sweating 3 1 Pruritus 3 0 Acne 2 1 Malaise 2 1 Arthritis 2 0 Treatment of Mildly to Moderately Active Ulcerative Colitis in Pediatric Patients 5 to 17 Years Old A randomized, double-blind, 6-week study of 2 dose levels of mesalamine delayed-release 400 mg tablets (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients were divided by body weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective body weight category) or a high dose (2.0, 3.6, and 4.8 g/day). The high dose is not an approved dosage because it was not found to be more effective than the approved dose [see Dosage and Administration (2.1) and Clinical Studies (14.1)]. Duration of exposure to mesalamine among the 82 patients in the study ranged from 12 to 50 days (mean of 40 days in each dose group). The majority (88%) of patients in each group were treated for more than 5 weeks. Table 2 provides a summary of the specific reported adverse reactions (ARs). Table 2: Adverse Reactions Reported in One Six-Week Trial (Study 3) Experienced by at Least 5% of Patients in the Low Dose Group or High Dose Group % of Patients with Adverse Reactions Low Dose High Dose Adverse Reaction (n=41) (n=41) Nasopharyngitis 15 12 Ulcerative Colitis 12 5 Headache 10 5 Abdominal pain 10 2 Dizziness 7 2 Sinusitis 7 0 Rash 5 5 Cough 5 0 Diarrhea 5 0 Fatigue 2 10 Pyrexia 0 7 Increased Lipase 0 5 Low Dose = mesalamine 400 mg delayed-release tablet 1.2 - 2.4 g/day; High Dose = mesalamine 400 mg delayed-release tablet 2.0 - 4.8 g/day. Dosage was dependent on body weight. Adverse Reactions reported at the 1-week telephone follow-up visit are included. Twelve percent of the patients in the low dose group and 5% of the patients in the high dose group had serious adverse reactions (ARs). Ulcerative colitis was reported as a serious AR in one subject in each group. Other serious ARs consisted of sinusitis, abdominal pain, decreased body mass index, adenovirus infection, bloody diarrhea, sclerosing cholangitis, and pancreatitis in one subject each in the low dose group and anemia and syncope in one subject each in the high dose group. Seven patients were withdrawn from the study because of ARs: 5 (12%) in the low dose group (ulcerative colitis, adenovirus infection, sclerosing cholangitis, pancreatitis) and 2 (5%) in the high dose group (increased amylase and increased lipase, upper abdominal pain). In general, the nature and severity of reactions in the pediatric population was similar to those reported in adult populations of patients with ulcerative colitis. Maintenance of Remission of Ulcerative Colitis in Adults In a 6-month placebo-controlled maintenance trial involving 264 patients (Study 4) 177 of whom were randomized to mesalamine delayed-release tablets, six (3.4%) of the patients using mesalamine delayed-release tablets discontinued therapy because of adverse reactions, as compared to four (4.6%) of patients using placebo [see Clinical Studies (14.2)]. The average age of patients in Study 4 was 42 years and 55% of patients were male. Adverse reactions leading to study withdrawal in patients using mesalamine delayed-release tablets included (each in one patient): anxiety; headache; pruritus; decreased libido; rheumatoid arthritis; and stomatitis and asthenia. In addition to reactions listed in Table 1, the following adverse reactions occurred in patients using mesalamine delayed-release tablets at a frequency of 2% or greater in Study 4: abdominal enlargement, gastroenteritis, gastrointestinal hemorrhage, infection, joint disorder, migraine, nervousness, paresthesia, rectal disorder, rectal hemorrhage, stool abnormalities, tenesmus, urinary frequency, vasodilation, and vision abnormalities. In 3342 patients in uncontrolled clinical studies, the following adverse reactions occurred at a frequency of 5% or greater and appeared to increase in frequency with increasing dose: asthenia, fever, flu syndrome, pain, abdominal pain, back pain, flatulence, gastrointestinal bleeding, arthralgia, and rhinitis. 6.2 Postmarketing Experience In addition to the adverse reactions reported above in clinical trials involving mesalamine delayed-release tablets, the adverse reactions listed below have been identified during post-approval use of mesalamine delayed-release tablets and other mesalamine-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Neck pain, facial edema, edema, lupus-like syndrome, drug fever. Cardiovascular: Pericarditis, myocarditis [see Warnings and Precautions (5.3)]. Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer bloody diarrhea. Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia, lymphadenopathy. Musculoskeletal: Gout. Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome. Renal: Renal failure, interstitial nephritis, minimal change nephropathy [see Warnings and Precautions (5.1)]. Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleuritis. Skin: Alopecia, psoriasis, pyoderma gangrenosus, dry skin, erythema nodosum, urticaria. Special Senses: Eye pain, taste perversion, blurred vision, tinnitus. Urogenital: Dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, reversible oligospermia. Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.
7 DRUG INTERACTIONS No formal drug interaction studies have been performed using DELZICOL with other drugs. However, the following interactions between mesalamine-containing products and other drugs have been reported. Nephrotoxic agents including NSAIDs: Renal reactions have been reported (7.1) Azathioprine or 6-mercaptopurine: Blood disorders have been reported (7.2) 7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of renal reactions [ see Warnings and Precautions (5.1)]. 7.2 Azathioprine or 6-mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders.
8 USE IN SPECIFIC POPULATIONS Renal Impairment: Use DELZICOL with caution in patients with a history of renal disease (5.1, 7.1, 8.6) Geriatric Patients: Monitor blood cell counts in geriatric patients (8.5) 8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well controlled studies of DELZICOL use in pregnant women. Limited published human data on mesalamine show no increase in the overall rate of congenital malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease. Furthermore, all pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. No evidence of fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose. DELZICOL should be used in pregnancy only if clearly needed. Human Data Mesalamine crosses the placenta. In prospective and retrospective studies of over 600 women exposed to mesalamine during pregnancy, the observed rate of congenital malformations was not increased above the background rate in the general population. Some data show an increased rate of preterm birth, stillbirth, and low birth weight, but it is unclear whether this was due to underlying maternal disease, drug exposure, or both, as active inflammatory bowel disease is also associated with adverse pregnancy outcomes. Animal data Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg/day. There was no evidence of impaired fertility or harm to the fetus. These mesalamine doses were about 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose, based on body surface area. 8.3 Nursing Mothers Mesalamine and its N-acetyl metabolite are present in human milk. In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on these concentrations, estimated infant daily doses for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DELZICOL and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Caution should be exercised when DELZICOL is administered to a nursing woman. 8.4 Pediatric Use The data presented in Section 8.4 are from clinical trials conducted with mesalamine 400 mg delayed-release tablets. DELZICOL is bioequivalent to these mesalamine delayed-release tablets. The safety and effectiveness of mesalamine delayed-release 400 mg tablets in pediatric patients 5 to 17 years of age for treatment of mildly to moderately active ulcerative colitis have been established over a 6-week period. Use of mesalamine delayed-release 400 mg tablets in these age groups is supported by evidence from adequate and well controlled studies of mesalamine delayed-release 400 mg tablets in adults and a single study in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. However, for patients less than 12 years of age, there is no age-appropriate formulation available. Therefore, DELZICOL is indicated for the treatment of mildly to moderately active ulcerative colitis for patients 12 years of age and older. Mesalamine delayed-release 400 mg tablets was studied in a randomized, double-blind, parallel-group, 6-week treatment study of two dose levels of mesalamine delayed-release 400 mg tablets in 82 pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients were divided by weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective weight category) or a high dose (2.0, 3.6, and 4.8 g/day). Baseline and screening visits were followed by a treatment period of 6 weeks [see Dosage and Administration (2.1)]. The high dose was not more effective than the low dose and is not an approved dosage [see Clinical Studies (14.1)]. The safety and effectiveness of DELZICOL in pediatric patients below the age of 5 years have not been established. The safety and effectiveness of DELZICOL in the maintenance of remission of ulcerative colitis in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of mesalamine delayed-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing DELZICOL. Reports from uncontrolled clinical studies and postmarketing reporting systems suggest a higher incidence of blood dyscrasias, that is, agranulocytosis, neutropenia, pancytopenia, in subjects receiving mesalamine delayed-release tablets who are 65 years or older. Caution should be taken to closely monitor blood cell counts during treatment with DELZICOL. 8.6 Renal Impairment Mesalamine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. It is recommended that all patients have an evaluation of renal function prior to initiation of DELZICOL therapy and periodically while on DELZICOL therapy [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].